These studies aim to accomplish three major goals: first to define how the structural and functional integrity of the epithelial barrier is disrupted by NS1;second, to identify specific interacting partners of NS1;and third, to define NS1 as a novel drug target that can be used to contain the H5N1 pandemic. The specific aims of this proposal are Aim 1: To test the hypothesis that NS1 disrupts barrier function of gut and lung epithelial cells, and Aim 2: To test the hypothesis that the PDZ motif of NS1 protein binds tight junction proteins and adherens junction proteins. These studies will use the following techniques: transepithelial resistance measuremets, inulin flux measurements, immunofluorescent staining, cell migration assays, and protein binding studies. Influenza virus H5N1 has the potential to become a global pandemic and has already claimed 204 lives worldwide. These studies will contribute to public health by allowing us to understand the role of the NS1 protein of H5N1 in disease pathogenesis and to identify NS1 as a target for novel drug therapies.